Coding exons function as tissue-specific enhancers of nearby genes

  1. Nadav Ahituv1,2,13
  1. 1Department of Bioengineering and Therapeutic Sciences,
  2. 2Institute for Human Genetics,
  3. 3Department of Anatomy,
  4. 4Program in Biomedical Sciences, University of California, San Francisco, California 94143, USA;
  5. 5The Morris Kahn Laboratory of Human Genetics, NIBN, Ben-Gurion University, Beer-Sheva 84105, Israel;
  6. 6Key Laboratory of Advanced Control and Optimization for Chemical Processes of the Ministry of Education, East China University of Science and Technology, Shanghai 200237, China;
  7. 7Department of Genetics,
  8. 8Department of Computer Science, Stanford University, Stanford, California 94305-5329, USA;
  9. 9Istituto di Genetica Medica, Università Cattolica S. Cuore, Rome 00168, Italy;
  10. 10JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA;
  11. 11Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, USA;
  12. 12Department of Developmental Biology, Stanford University, Stanford, California 94305-5329, USA

    Abstract

    Enhancers are essential gene regulatory elements whose alteration can lead to morphological differences between species, developmental abnormalities, and human disease. Current strategies to identify enhancers focus primarily on noncoding sequences and tend to exclude protein coding sequences. Here, we analyzed 25 available ChIP-seq data sets that identify enhancers in an unbiased manner (H3K4me1, H3K27ac, and EP300) for peaks that overlap exons. We find that, on average, 7% of all ChIP-seq peaks overlap coding exons (after excluding for peaks that overlap with first exons). By using mouse and zebrafish enhancer assays, we demonstrate that several of these exonic enhancer (eExons) candidates can function as enhancers of their neighboring genes and that the exonic sequence is necessary for enhancer activity. Using ChIP, 3C, and DNA FISH, we further show that one of these exonic limb enhancers, Dync1i1 exon 15, has active enhancer marks and physically interacts with Dlx5/6 promoter regions 900 kb away. In addition, its removal by chromosomal abnormalities in humans could cause split hand and foot malformation 1 (SHFM1), a disorder associated with DLX5/6. These results demonstrate that DNA sequences can have a dual function, operating as coding exons in one tissue and enhancers of nearby gene(s) in another tissue, suggesting that phenotypes resulting from coding mutations could be caused not only by protein alteration but also by disrupting the regulation of another gene.

    Footnotes

    • Received October 19, 2011.
    • Accepted March 19, 2012.

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